DOCSLIB.ORG

Identification of Whole Cell Active Molecules of Mycobacterium Tuberculosis, Elucidation of Molecular Mechanisms Responsible

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Identification of Whole Cell Active Molecules of Mycobacterium Tuberculosis, Elucidation of Molecular Mechanisms Responsible IDENTIFICATION OF WHOLE CELL ACTIVE MOLECULES OF MYCOBACTERIUM TUBERCULOSIS, ELUCIDATION OF MOLECULAR MECHANISMS RESPONSIBLE FOR RESISTANCE, AND CHARACTERIZATION OF RV0272: A POTENTIAL THERAPEUTIC TARGET A Dissertation by RYAN C. HUGHES Submitted to the Office of Graduate and Professional Studies of Texas A&M University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Chair of Committee: James C. Sacchettini Committee Members: Tadhg Begley Paul Straight Hays Rye Head of Department: Gregory D. Reinhart December 2016 Major Subject: Biochemistry Copyright 2016 Ryan C. Hughes ABSTRACT Current therapies for treatment of mycobacterial infections are adequate when diagnosis and pathology is well defined. Yet more evidence is beginning to accumulate for the multitude of reasons behind drug insensitive mycobacterial cases, especially for Mycobacterium tuberculosis (M. tuberculosis). Drug resistant strains are not always the sole cause for complications in treatment. Heterogeneity of bacterial sub-populations and the micro environments they reside in can contribute to mycobacteria’s ability to evade treatment. Elucidation of the mechanisms essential for bacterial virulence and persistence as well as developing antibiotics with more diverse mechanisms of action will allow clinicians to make more effective decisions regarding treatment regimens for each individual pathology. One of the first stages in drug development is the identification of small molecules which effectively inhibit bacterial growth as well as determining their mechanism of action. The first part of this study focuses on establishing a High Throughput Screening (HTS) assay for the identification of growth inhibitors of M. tuberculosis, Mycobacterium smegmatis (M. smegmatis), Mycobacterium abscessus (M. abscessus), and Mycobacterium fortuitum (M. fortuitum). Pathogenesis is not exclusive to M. tuberculosis and these other non-tubercular species not only contribute to the disease epidemic, but can also serve as model organism(s) in a laboratory setting for M. tuberculosis due to their rapid growth rate and low infectivity in healthy individuals. A HTS of over 100,000 molecules was carried out against M. tuberculosis, M. fortuitum, and M. abscessus. The identified hits were validated in a dose response assay and ii attempts to identify the intracellular target of inhibition were determined via selection of resistant mutants in M. smegmatis, M. abscessus, and M. fortuitum. The second part of this study focuses on the characterization of a protein identified as a potential target of a growth inhibitor of M. tuberculosis identified in the original HTS. This enzyme, Rv0272, encodes for a hypothetical α/β hydrolase and has no significant sequence homology to any previously characterized enzymes. Purified recombinant Rv0272 was biochemically and biophysically characterized. The crystal structures of ligand bound Rv0272 combined with binding studies revealed the ligand promiscuity of Rv0272 and provided clues for potential enzymatic function(s). The enzyme has demonstrated binding affinity for small dicarboxylic acids, especially methylmalonate, phthalate, and maleate. Moreover, products of enzyme mediated reactions were observed in the active site of solved crystal structures after soaking with metabolites. These results suggest that Rv0272 is a previously uncharacterized serine hydrolase that may be functioning in the B12-dependent methylmalonate pathway for degradation of odd chain fatty acids. Additionally, Rv0272 may moonlight as an amidase, esterase, and/or thioesterase under certain physiological conditions. iii DEDICATION I would like to dedicate this work to my parents for their limitless support, love and patience throughout the years and for always being there for me my entire life and especially while I finish my degree. iv ACKNOWLEDGEMENTS First and foremost I would like to thank my committee chair, Dr. Sacchettini for giving me the opportunity to be a part of his lab and conduct this research. I would especially like to thank him for allowing me to choose my own path, and develop this body of work through many of my own ideas and curiosities. It has been an incredible learning experience. I would like to thank the many wonderful individuals I have had the pleasure of working with throughout the years, not only on this project but on other collaborations as well: Dr. Eric Rubin at Harvard School of Public Health, Dr. Chris Sassetti and Dr Subbu Nambi of University of Massachusetts Medical School, Dr. Miriam Braunstein Of University of North Carolina at Chapel Hill School of Medicine, Dr. Tom Ioerger and Dr. Inna Krieger of Texas A&M University, Dr. John Markley, Dr. David Aceti, and Dr. Jaime Stark of University of Wisconsin-Madison. I would especially like to thank all the members/ collaborators of FLUTE. It has been a pleasure working with all of you and I always look forward to our meetings every fall. Finally, I would like to thank all my lab mates, my friends, and my family, especially my parents. I would not have made it this far if it wasn’t for your constant support, encouragement, and the occasional happy hour conversation. v TABLE OF CONTENTS Page ABSTRACT ....................................................................................................................... ii DEDICATION .................................................................................................................. iv ACKNOWLEDGEMENTS ............................................................................................... v TABLE OF CONTENTS .................................................................................................. vi LIST OF FIGURES ........................................................................................................... xi LIST OF TABLES ........................................................................................................... xv CHAPTER I INTRODUCTION ........................................................................................ 1 History of Tuberculosis .......................................................................................... 1 History of Antibacterial Chemotherapeutics .......................................................... 3 History of Tuberculosis Treatment ........................................................................ 8 Current Treatment .................................................................................................. 8 First-line Antibiotics for Drug-Susceptible M. tuberculosis ................................ 11 Isoniazid (INH) ........................................................................................ 11 General Information, Dosage, Adverse Effects............................ 11 Discovery ..................................................................................... 11 Mode of Action ............................................................................ 13 Mechanism of Resistance ............................................................. 16 Ethambutol (EMB) ................................................................................... 18 General Information, Dosage, Adverse Effects............................ 18 Discovery ..................................................................................... 20 Mode of Action ............................................................................ 21 Mechanism of Resistance ............................................................. 22 Rifampicin (RIF) ...................................................................................... 23 General Information, Dosage, Adverse Effects............................ 23 Discovery ..................................................................................... 24 Mode of Action ............................................................................ 25 Mechanism of Resistance ............................................................. 27 Pyrazinamide (PZA) ................................................................................. 28 General Information, Dosage, Adverse Effects............................ 28 Discovery ..................................................................................... 28 vi Mode of Action ............................................................................ 30 Mechanism of Resistance ............................................................. 32 Second-line Drugs for Treatment of MDR-TB and XDR-TB ............................. 33 Streptomycin (SM) ................................................................................... 33 General Information, Dosage, Adverse Effects............................ 33 Discovery ..................................................................................... 33 Mode of Action ............................................................................ 34 Mechanism of Resistance ............................................................. 35 Ethionamide (ETH) .................................................................................. 36 General Information, Dosage, Adverse Effects............................ 36 Discovery ..................................................................................... 36 Mode of Action ............................................................................ 37 Mechanism of Resistance ............................................................. 38 Para-aminosalicylic Acid (PAS) .............................................................
Load more

Recommended publications
  • Analysis of Mutations Leading to Para-Aminosalicylic Acid Resistance in Mycobacterium Tuberculosis
    www.nature.com/scientificreports OPEN Analysis of mutations leading to para-aminosalicylic acid resistance in Mycobacterium tuberculosis Received: 9 April 2019 Bharati Pandey1, Sonam Grover2, Jagdeep Kaur1 & Abhinav Grover3 Accepted: 31 July 2019 Thymidylate synthase A (ThyA) is the key enzyme involved in the folate pathway in Mycobacterium Published: xx xx xxxx tuberculosis. Mutation of key residues of ThyA enzyme which are involved in interaction with substrate 2′-deoxyuridine-5′-monophosphate (dUMP), cofactor 5,10-methylenetetrahydrofolate (MTHF), and catalytic site have caused para-aminosalicylic acid (PAS) resistance in TB patients. Focusing on R127L, L143P, C146R, L172P, A182P, and V261G mutations, including wild-type, we performed long molecular dynamics (MD) simulations in explicit solvent to investigate the molecular principles underlying PAS resistance due to missense mutations. We found that these mutations lead to (i) extensive changes in the dUMP and MTHF binding sites, (ii) weak interaction of ThyA enzyme with dUMP and MTHF by inducing conformational changes in the structure, (iii) loss of the hydrogen bond and other atomic interactions and (iv) enhanced movement of protein atoms indicated by principal component analysis (PCA). In this study, MD simulations framework has provided considerable insight into mutation induced conformational changes in the ThyA enzyme of Mycobacterium. Antimicrobial resistance (AMR) threatens the efective treatment of tuberculosis (TB) caused by the bacteria Mycobacterium tuberculosis (Mtb) and has become a serious threat to global public health1. In 2017, there were reports of 5,58000 new TB cases with resistance to rifampicin (frst line drug), of which 82% have developed multidrug-resistant tuberculosis (MDR-TB)2. AMR has been reported to be one of the top health threats globally, so there is an urgent need to proactively address the problem by identifying new drug targets and understanding the drug resistance mechanism3,4.
    [Show full text]
  • Rifalazil | Medchemexpress
    Inhibitors Product Data Sheet Rifalazil • Agonists Cat. No.: HY-105099 CAS No.: 129791-92-0 Molecular Formula: C₅₁H₆₄N₄O₁₃ • Molecular Weight: 941.07 Screening Libraries Target: DNA/RNA Synthesis; Bacterial Pathway: Cell Cycle/DNA Damage; Anti-infection Storage: 4°C, sealed storage, away from moisture * In solvent : -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture) SOLVENT & SOLUBILITY In Vitro DMSO : 8.33 mg/mL (8.85 mM; Need ultrasonic) Mass Solvent 1 mg 5 mg 10 mg Concentration Preparing 1 mM 1.0626 mL 5.3131 mL 10.6262 mL Stock Solutions 5 mM 0.2125 mL 1.0626 mL 2.1252 mL 10 mM --- --- --- Please refer to the solubility information to select the appropriate solvent. In Vivo 1. Add each solvent one by one: 10% DMSO >> 40% PEG300 >> 5% Tween-80 >> 45% saline Solubility: ≥ 2.2 mg/mL (2.34 mM); Clear solution 2. Add each solvent one by one: 10% DMSO >> 90% (20% SBE-β-CD in saline) Solubility: ≥ 2.2 mg/mL (2.34 mM); Clear solution BIOLOGICAL ACTIVITY Description Rifalazil (KRM-1648; ABI-1648), a rifamycin derivative, inhibits the bacterial DNA-dependent RNA polymerase and kills bacterial cells by blocking off the β-subunit in RNA polymerase[1]. Rifalazil (KRM-1648; ABI-1648) is an antibiotic, exhibits high potency against mycobacteria, gram-positive bacteria, Helicobacter pylori, C. pneumoniae and C. trachomatis with MIC values from 0.00025 to 0.0025 μg/ml[3]. Rifalazil (KRM-1648; ABI-1648) has the potential for the treatment of Chlamydia infection, Clostridium difficile associated diarrhea (CDAD), and tuberculosis (TB)[2].
    [Show full text]
  • EMA/CVMP/158366/2019 Committee for Medicinal Products for Veterinary Use
    Ref. Ares(2019)6843167 - 05/11/2019 31 October 2019 EMA/CVMP/158366/2019 Committee for Medicinal Products for Veterinary Use Advice on implementing measures under Article 37(4) of Regulation (EU) 2019/6 on veterinary medicinal products – Criteria for the designation of antimicrobials to be reserved for treatment of certain infections in humans Official address Domenico Scarlattilaan 6 ● 1083 HS Amsterdam ● The Netherlands Address for visits and deliveries Refer to www.ema.europa.eu/how-to-find-us Send us a question Go to www.ema.europa.eu/contact Telephone +31 (0)88 781 6000 An agency of the European Union © European Medicines Agency, 2019. Reproduction is authorised provided the source is acknowledged. Introduction On 6 February 2019, the European Commission sent a request to the European Medicines Agency (EMA) for a report on the criteria for the designation of antimicrobials to be reserved for the treatment of certain infections in humans in order to preserve the efficacy of those antimicrobials. The Agency was requested to provide a report by 31 October 2019 containing recommendations to the Commission as to which criteria should be used to determine those antimicrobials to be reserved for treatment of certain infections in humans (this is also referred to as ‘criteria for designating antimicrobials for human use’, ‘restricting antimicrobials to human use’, or ‘reserved for human use only’). The Committee for Medicinal Products for Veterinary Use (CVMP) formed an expert group to prepare the scientific report. The group was composed of seven experts selected from the European network of experts, on the basis of recommendations from the national competent authorities, one expert nominated from European Food Safety Authority (EFSA), one expert nominated by European Centre for Disease Prevention and Control (ECDC), one expert with expertise on human infectious diseases, and two Agency staff members with expertise on development of antimicrobial resistance .
    [Show full text]
  • Reseptregisteret 2012–2016 the Norwegian Prescription Database 2012–2016
    2017:2 LEGEMIDDELSTATISTIKK Reseptregisteret 2012–2016 The Norwegian Prescription Database 2012–2016 ISSN 1890-9647 Reseptregisteret 2012–2016 The Norwegian Prescription Database 2012–2016 Christian Lie Berg (redaktør) Hege Salvesen Blix Olaug Fenne Kari Furu Vidar Hjellvik Kari Jansdotter Husabø Per Olav Kormeset Solveig Sakshaug Hanne Strøm Sissel Torheim Utgitt av Folkehelseinstituttet / Published by the Norwegian Institute of Public Health Området for Psykisk og fysisk helse Avdeling for Legemiddelepidemiologi April 2017 Tittel/Title: Legemiddelstatistikk 2017:2 Reseptregisteret 2012–2016 / The Norwegian Prescription Database 2012–2016 Forfattere/Authors: Christian Lie Berg (redaktør) Hege Salvesen Blix Olaug Fenne Kari Furu Vidar Hjellvik Kari Jansdotter Husabø Per Olav Kormeset Solveig Sakshaug Hanne Strøm Sissel Torheim Bestilling/Order: Rapporten kan lastes ned som pdf på Folkehelseinstituttets nettsider: www.fhi.no/ The report is available as pdf format only and can be downloaded from www.fhi.no Layout omslag: www.fetetyper.no Layout/design, innhold: Houston 911 Kontaktinformasjon/Contact information: Folkehelseinstituttet/Norwegian Institute of Public Health P.O.Box 4404 Nydalen N-0403 Oslo Tel: +47 21 07 70 00 ISSN: 1890-9647 ISBN 978-82-8082-824-8 elektronisk utgave Sitering/Citation: Berg, C (red), Reseptregisteret 2012–2016 [The Norwegian Prescription Database 2012–2016] Legemiddelstatistikk 2017:2, Oslo, Norge: Folkehelseinstituttet, 2017. Tidligere utgaver / Previous editions: 2008: Reseptregisteret 2004–2007 / The Norwegian
    [Show full text]
  • Estonian Statistics on Medicines 2016 1/41
    Estonian Statistics on Medicines 2016 ATC code ATC group / Active substance (rout of admin.) Quantity sold Unit DDD Unit DDD/1000/ day A ALIMENTARY TRACT AND METABOLISM 167,8985 A01 STOMATOLOGICAL PREPARATIONS 0,0738 A01A STOMATOLOGICAL PREPARATIONS 0,0738 A01AB Antiinfectives and antiseptics for local oral treatment 0,0738 A01AB09 Miconazole (O) 7088 g 0,2 g 0,0738 A01AB12 Hexetidine (O) 1951200 ml A01AB81 Neomycin+ Benzocaine (dental) 30200 pieces A01AB82 Demeclocycline+ Triamcinolone (dental) 680 g A01AC Corticosteroids for local oral treatment A01AC81 Dexamethasone+ Thymol (dental) 3094 ml A01AD Other agents for local oral treatment A01AD80 Lidocaine+ Cetylpyridinium chloride (gingival) 227150 g A01AD81 Lidocaine+ Cetrimide (O) 30900 g A01AD82 Choline salicylate (O) 864720 pieces A01AD83 Lidocaine+ Chamomille extract (O) 370080 g A01AD90 Lidocaine+ Paraformaldehyde (dental) 405 g A02 DRUGS FOR ACID RELATED DISORDERS 47,1312 A02A ANTACIDS 1,0133 Combinations and complexes of aluminium, calcium and A02AD 1,0133 magnesium compounds A02AD81 Aluminium hydroxide+ Magnesium hydroxide (O) 811120 pieces 10 pieces 0,1689 A02AD81 Aluminium hydroxide+ Magnesium hydroxide (O) 3101974 ml 50 ml 0,1292 A02AD83 Calcium carbonate+ Magnesium carbonate (O) 3434232 pieces 10 pieces 0,7152 DRUGS FOR PEPTIC ULCER AND GASTRO- A02B 46,1179 OESOPHAGEAL REFLUX DISEASE (GORD) A02BA H2-receptor antagonists 2,3855 A02BA02 Ranitidine (O) 340327,5 g 0,3 g 2,3624 A02BA02 Ranitidine (P) 3318,25 g 0,3 g 0,0230 A02BC Proton pump inhibitors 43,7324 A02BC01 Omeprazole
    [Show full text]
  • Anew Drug Design Strategy in the Liht of Molecular Hybridization Concept
    www.ijcrt.org © 2020 IJCRT | Volume 8, Issue 12 December 2020 | ISSN: 2320-2882 “Drug Design strategy and chemical process maximization in the light of Molecular Hybridization Concept.” Subhasis Basu, Ph D Registration No: VB 1198 of 2018-2019. Department Of Chemistry, Visva-Bharati University A Draft Thesis is submitted for the partial fulfilment of PhD in Chemistry Thesis/Degree proceeding. DECLARATION I Certify that a. The Work contained in this thesis is original and has been done by me under the guidance of my supervisor. b. The work has not been submitted to any other Institute for any degree or diploma. c. I have followed the guidelines provided by the Institute in preparing the thesis. d. I have conformed to the norms and guidelines given in the Ethical Code of Conduct of the Institute. e. Whenever I have used materials (data, theoretical analysis, figures and text) from other sources, I have given due credit to them by citing them in the text of the thesis and giving their details in the references. Further, I have taken permission from the copyright owners of the sources, whenever necessary. IJCRT2012039 International Journal of Creative Research Thoughts (IJCRT) www.ijcrt.org 284 www.ijcrt.org © 2020 IJCRT | Volume 8, Issue 12 December 2020 | ISSN: 2320-2882 f. Whenever I have quoted written materials from other sources I have put them under quotation marks and given due credit to the sources by citing them and giving required details in the references. (Subhasis Basu) ACKNOWLEDGEMENT This preface is to extend an appreciation to all those individuals who with their generous co- operation guided us in every aspect to make this design and drawing successful.
    [Show full text]
  • Pharmaceutical Appendix to the Tariff Schedule 2
    Harmonized Tariff Schedule of the United States (2007) (Rev. 2) Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE Harmonized Tariff Schedule of the United States (2007) (Rev. 2) Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE TARIFF SCHEDULE 2 Table 1. This table enumerates products described by International Non-proprietary Names (INN) which shall be entered free of duty under general note 13 to the tariff schedule. The Chemical Abstracts Service (CAS) registry numbers also set forth in this table are included to assist in the identification of the products concerned. For purposes of the tariff schedule, any references to a product enumerated in this table includes such product by whatever name known. ABACAVIR 136470-78-5 ACIDUM LIDADRONICUM 63132-38-7 ABAFUNGIN 129639-79-8 ACIDUM SALCAPROZICUM 183990-46-7 ABAMECTIN 65195-55-3 ACIDUM SALCLOBUZICUM 387825-03-8 ABANOQUIL 90402-40-7 ACIFRAN 72420-38-3 ABAPERIDONUM 183849-43-6 ACIPIMOX 51037-30-0 ABARELIX 183552-38-7 ACITAZANOLAST 114607-46-4 ABATACEPTUM 332348-12-6 ACITEMATE 101197-99-3 ABCIXIMAB 143653-53-6 ACITRETIN 55079-83-9 ABECARNIL 111841-85-1 ACIVICIN 42228-92-2 ABETIMUSUM 167362-48-3 ACLANTATE 39633-62-0 ABIRATERONE 154229-19-3 ACLARUBICIN 57576-44-0 ABITESARTAN 137882-98-5 ACLATONIUM NAPADISILATE 55077-30-0 ABLUKAST 96566-25-5 ACODAZOLE 79152-85-5 ABRINEURINUM 178535-93-8 ACOLBIFENUM 182167-02-8 ABUNIDAZOLE 91017-58-2 ACONIAZIDE 13410-86-1 ACADESINE 2627-69-2 ACOTIAMIDUM 185106-16-5 ACAMPROSATE 77337-76-9
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 8,097,607 B2 Cabana Et Al
    USO08097607B2 (12) United States Patent (10) Patent No.: US 8,097,607 B2 Cabana et al. (45) Date of Patent: *Jan. 17, 2012 (54) LOW DOSE RIFALAZIL COMPOSITIONS Emori et al., “Evaluation of in Vivo Therapeutic Efficacy of a New Benzoxazinorifamycin, KRM-1648, in SCID Mouse Model for Dis (76) Inventors: Bernard E. Cabana, Montgomery seminated Mycobacterium avium Complex Infection.” International Village, MD (US); Arthur F. Michaelis, Journal of Antimicrobial Agents 10(1):59 (1998). Devon, PA (US); Gary P. Magnant, Fujii et al., “In Vitro and In Vivo Antibacterial Activities of KRM Topsfield, MA (US); Chalom B. 1648 and KRM-1657, New Rifamycin Derivatives.” Antimicrobial Sayada, Luxembourg (LU) Agents and Chemotherapy 38: 1118, (1994). Gidoh et al., “Bactericidal Action at Low Doses of a New Rifamycin (*) Notice: Subject to any disclaimer, the term of this Derivative, 3'-hydroxy-5'-(4-isobutyl-1-piperazinyl) patent is extended or adjusted under 35 Benzoxazinorifamycin (KRM-1648) on Mycobacterium leprae U.S.C. 154(b) by 447 days. Inoculated into Ffootpads of Nude Mice.” Leprosy Review 63(4):319 This patent is Subject to a terminal dis (1992). claimer. Heep et al., “Detection of Rifabutin Resistance and Association of rpoB Mutation S with Resistance to Four Rifamycin Derivatives in Helicobacter pylori.” Journal of Clinical Microbiology & Infectious (21) Appl. No.: 10/668,792 Diseases 21:143 (2002). Hirara et al., “In Vitro and in Vivo Activities of the (22) Filed: Sep. 23, 2003 Benezoxazinorifamycin KRM-1648 Against Mycobacterium tuber (65) Prior Publication Data culosis,” Antimocrobial Agents and Chemotherapy 39 (10):2295 (1995). US 2004/O15784.0 A1 Aug.
    [Show full text]
  • Preliminary Results of Bedaquiline As Salvage Therapy for Patients with Nontuberculous Mycobacterial Lung Disease
    [ Original Research Chest Infections ] Preliminary Results of Bedaquiline as Salvage Th erapy for Patients With Nontuberculous Mycobacterial Lung Disease Julie V. Philley , MD ; Richard J. Wallace Jr , MD , FCCP ; Jeana L. Benwill , MD ; Varsha Taskar , MD ; Barbara A. Brown-Elliott , MS , MT(ASCP)SM ; Foram Thakkar , MBBS ; Timothy R. Aksamit , MD , FCCP ; and David E. Griffi th , MD , FCCP BACKGROUND: Bedaquiline is an oral antimycobacterial agent belonging to a new class of drugs called diarylquinolines. It has low equivalent minimal inhibitory concentration s for Mycobacterium tuberculosis and nontuberculous mycobacterial (NTM) lung disease , especially Mycobacterium avium complex (MAC) and Mycobacterium abscessus (Mab). Bedaquiline appears to be eff ective for the treatment of multidrug-resistant TB but has not been tested clinically for NTM disease. METHODS: We describe a case series of off -label use of bedaquiline for treatment failure lung disease caused by MAC or Mab. Only patients whose insurance would pay for the drug were included. Fift een adult patients were selected, but only 10 (six MAC, four Mab) could obtain bedaquiline. Th e 10 patients had been treated for 1 to 8 years, and all were on treatment at the start of bedaquiline therapy. Eighty percent had macrolide-resistant isolates (eight of 10). Th e patients were treated with the same bedaquiline dosage as that used in TB trials and received the best available companion drugs (mean, 5.0 drugs). All patients completed 6 months of therapy and remain on bedaquiline. RESULTS: Common side eff ects included nausea (60%), arthralgias (40%), and anorexia and subjective fever (30%). No abnormal ECG fi ndings were observed with a mean corrected QT interval lengthening of 2.4 milliseconds at 6 months.
    [Show full text]
  • BMJ Open Is Committed to Open Peer Review. As Part of This Commitment We Make the Peer Review History of Every Article We Publish Publicly Available
    BMJ Open is committed to open peer review. As part of this commitment we make the peer review history of every article we publish publicly available. When an article is published we post the peer reviewers’ comments and the authors’ responses online. We also post the versions of the paper that were used during peer review. These are the versions that the peer review comments apply to. The versions of the paper that follow are the versions that were submitted during the peer review process. They are not the versions of record or the final published versions. They should not be cited or distributed as the published version of this manuscript. BMJ Open is an open access journal and the full, final, typeset and author-corrected version of record of the manuscript is available on our site with no access controls, subscription charges or pay-per-view fees (http://bmjopen.bmj.com). If you have any questions on BMJ Open’s open peer review process please email [email protected] BMJ Open Pediatric drug utilization in the Western Pacific region: Australia, Japan, South Korea, Hong Kong and Taiwan Journal: BMJ Open ManuscriptFor ID peerbmjopen-2019-032426 review only Article Type: Research Date Submitted by the 27-Jun-2019 Author: Complete List of Authors: Brauer, Ruth; University College London, Research Department of Practice and Policy, School of Pharmacy Wong, Ian; University College London, Research Department of Practice and Policy, School of Pharmacy; University of Hong Kong, Centre for Safe Medication Practice and Research, Department
    [Show full text]
  • Treatment of Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis in Children: the Role of Bedaquiline and Delamanid
    microorganisms Review Treatment of Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis in Children: The Role of Bedaquiline and Delamanid Francesco Pecora, Giulia Dal Canto, Piero Veronese and Susanna Esposito * Pediatric Clinic, Department of Medicine and Surgery, Pietro Barille Children’s Hospital, University Hospital of Parma, 43126 Parma, Italy; [email protected] (F.P.); [email protected] (G.D.C.); [email protected] (P.V.) * Correspondence: [email protected] Abstract: Multidrug-resistant (MDR) tuberculosis (TB) has been emerging at an alarming rate over the last few years. It has been estimated that about 3% of all pediatric TB is MDR, meaning about 30,000 cases each year. Although most children with MDR-TB can be successfully treated, up to five years ago effective treatment was associated with a high incidence of severe adverse effects and patients with extensively drug-resistant (XDR) TB had limited treatment options and no standard regimen. The main objective of this manuscript is to discuss our present knowledge of the management of MDR- and XDR-TB in children, focusing on the characteristics and available evidence on the use of two promising new drugs: bedaquiline and delamanid. PubMed was used to search for all of the studies published up to November 2020 using key words such as “bedaquiline” and “delamanid” and “children” and “multidrug-resistant tuberculosis” and “extensively drug-resistant tuberculosis”. The search was limited to articles published in English and providing evidence-based Citation: Pecora, F.; Dal Canto, G.; data. Although data on pediatric population are limited and more studies are needed to confirm Veronese, P.; Esposito, S.
    [Show full text]
  • THE PRICE of BEDAQUILINE by Lindsay Mckenna | Edited By: Erica Lessem, Mike Frick, and Marcus Low
    [email protected] THE PRICE OF BEDAQUILINE By Lindsay McKenna | Edited by: Erica Lessem, Mike Frick, and Marcus Low INTRODUCTION In December 2012, bedaquiline (Sirturo) became the first new tuberculosis (TB) drug from a new drug class to receive approval by the U.S. Food and Drug Administration (FDA) in 40 years. Since then, uptake of this important drug has been far below the global need. An August 2018 update to the World Health Organization (WHO) guidelines designated bedaquiline as a core component of treatment regimens for rifampicin-resistant and multidrug-resistant TB (RR-/MDR-TB).1 As a result, even broader access to bedaquiline is now needed. Among barriers to bedaquiline access, affordability is a major concern, as the global donation program set up by the drug’s sponsor, Janssen, a subsidiary of Johnson & Johnson, ends in March 2019. THE PRICE OF BEDAQUILINE (AND ITS EVOLUTION) Pre-donation program: Janssen initially established a tiered pricing structure for bedaquiline. The price for a six-month course of bedaquiline was different for low-, middle-, and high-income countries (US$900, $3,000, and $30,000, respectively). Donation program: In 2014, to facilitate the uptake of bedaquiline, Janssen and the U.S. Agency for International Development (USAID) set up a temporary global donation program. Under this donation program, most countries eligible to receive funding from the Global Fund could procure bedaquiline for free, via the Global Drug Facility (GDF). The program initially covered 30,000 treatment courses, all of which were claimed by July 2018. USAID and Janssen then made an additional 30,000 courses available until March 2019 (or when those 30,000 courses are claimed, whichever came first).
    [Show full text]